Aging in human subjects is associated with heightened susceptibility to injury triggered by ischemia/reperfusion (I/R). Fundamental metabolic and biochemical changes occur in aging tissues in the basal state, and consequent to I/R. Aged human and Fischer 344 rat hearts display increased accumulation of Advanced Glycation Endproducts (AGEs), the products of nonenzymatic glycation/oxidation of proteins/lipids. AGEs may impart gain of function in the tissues by virtue of their ability to trigger signaling pathways, via Receptor for AGE (RAGE). In human aging, in the absence of overt cardiovascular disease or diabetes, increased expression/activity of the key polyol pathway enzyme aldose reductase (AR) occurs, leading to multiple metabolic disturbances, including generation of methylglyoxal (MG) and 3- deoxyglucosone (3-DG), precursors of AGEs. Aged human hearts, in the absence of cardiovascular disease or risk factors, display increased expression of RAGE antigen vs. young hearts. Our preliminary data reveal that myocardium of aged Fischer 344 rats (age, 24 mos), displays increased RAGE antigen compared to young rats (age, 4 months), particularly in endothelial cells (EC) and cardiomyocytes. Pharmacological blockade of RAGE in aged Fischer 344 rats attenuates I/R injury in the isolated perfused heart. Thus, we hypothesize that in aging, accumulation of AGEs upregulates expression of RAGE, thereby establishing basal dysfunction. Upon superimposed I/R, augmented ligand-RAGE mechanisms set the stage for enhanced biochemical and inflammatory stress and impairment in metabolism. Together, these forces converge to magnify I/R injury. We will test these concepts in aged Fischer 344 rats and RAGE mutant mice. These studies will be built on the premise that pharmacological blockade of RAGE may represent a potent strategy for the prevention of age-related cardiovascular dysfunction. Project 2 is closely linked to Projects 1&3, as each studies aging-linked enhanced vulnerability to I/R in the intact heart and isolated EC and cardiomyocytes, respectively. Project 2 shares mouse/rat models with Projects 1 and 3. Project 2 will utilize all three Cores of the Program Project during all five years of the grant.